The overall aim of this R21 resubmission is to optimize and test the efficacy of a paramyosin based vaccine against bovine schistosomiasis japonica. The goal of this vaccine is to reduce animal disease and reduce transmission of schistosomiasis to humans. Schistosomiasis, caused by three principle species of dioecious trematodes (flatworms), currently infects over 250 million individuals, results in an estimated 2-15% chronic disability, and contributes to poor health and economic stagnation in endemic areas. Although schistosomiasis is effectively treated with Praziquantel (PZQ), rapid reinfection with rebound morbidity precludes effective control based on chemotherapy alone and justifies current efforts to develop vaccines for these parasites. Amongst the species of schistosomes that infect humans, S. japonicum is unique in having significant animal reservoirs that contribute to human transmission and two recent studies have demonstrated that drug curing or eliminating water buffalos in endemic areas can profoundly reduce, by 75 to 93%, transmission of S. japonicum to humans. In our recent pilot experiments, vaccination of water buffalo with recombinant, full length paramyosin in Montanide ISA 206 resulted in 52% reduction in median worm burden after cercarial challenge compared to buffalo treated with adjuvant alone. We propose to accelerate the development of paramyosin as a vaccine for both human and bovine schistosomiasis by conducting safety and efficacy trials in water buffaloes, a large animal model of schistosomiasis. A successful bovine vaccine would: 1) have direct veterinary application, 2) directly reduce transmission to humans, and 3) serve as a non-rodent large animal model supporting an FDA IND application to initiate Phase I/II trials of a paramyosin based vaccine in humans.